title: Radiologic Responses in Cynomolgus Macaques for Assessing Tuberculosis Chemotherapy Regimens.
abstract: Trials to test new drugs currently in development against tuberculosis in humans are impractical. All animal models to prioritize new regimens are imperfect, but nonhuman primates (NHPs) infected withMycobacterium tuberculosisdevelop active tuberculosis (TB) disease with a full spectrum of lesion types seen in humans. Serial 2-deoxy-2-[18F]-fluoro-d-glucose (FDG) positron emission tomography (PET) with computed tomography (CT) imaging was performed on cynomolgus macaques during infection and chemotherapy with individual agents or the four-drug combination therapy most widely used globally. The size and metabolic activity of lung granulomas varied among animals and even within a single animal during development of disease. Individual granulomas within untreated animals had highly local and independent outcomes, some progressing in size and FDG uptake, while others waned, illustrating the highly dynamic nature of active TB. At necropsy, even untreated animals were found to have a proportion of sterile lesions consistent with the dynamics of this infection. A more marked reduction in overall metabolic activity in the lungs (decreased FDG uptake) was associated with effective treatment. A reduction in the size of individual lesions correlated with a lower bacterial burden at necropsy. Isoniazid treatment was associated with a transient increase in metabolic activity in individual lesions, whereas a net reduction occurred in most lesions from rifampin-treated animals. Quadruple-drug therapy resulted in the highest decrease in FDG uptake. The findings of PET-CT imaging may provide an important early correlate of the efficacy of novel combinations of new drugs that can be directly translated to human clinical trials.
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Philana Ling
authors.initials: PL
authors.lastname: Lin
authors.affiliation: Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Coleman
authors.affiliation: Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
authors.forename: Jonathan P J
authors.initials: JP
authors.lastname: Carney
authors.affiliation: Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Lopresti
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Jaime
authors.initials: J
authors.lastname: Tomko
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Fillmore
authors.affiliation: Department of Medicine, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USA.
authors.forename: Veronique
authors.initials: V
authors.lastname: Dartois
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.|Center for Vaccine Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Scanga
authors.affiliation: Center for Vaccine Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: L James
authors.initials: LJ
authors.lastname: Frye
authors.affiliation: Division of Laboratory Animal Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Janssen
authors.affiliation: Division of Laboratory Animal Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Edwin
authors.initials: E
authors.lastname: Klein
authors.affiliation: Tuberculosis Research Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Clifton E
authors.initials: CE
authors.lastname: Barry
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA joanne@pitt.edu.|Center for Vaccine Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: JoAnne L
authors.initials: JL
authors.lastname: Flynn